Abstract

Pain is a sense that has two purposes in humans: first, to warn of impending tissue damage and detect actual tissue damage
– a process known as nociception; and second to guide childhood and adolescent development by setting upper limits to activity.
A complete absence of pain sensing is found in a small number of Mendelian disorders. These disorders of painlessness can
be categorised into three categories: defects in peripheral nervous system development, disorders in pain sensing and progressive
nociceptor‐specific neuropathies. The study of these conditions has helped to sculpt our understanding of the human pain sensing
systems and provided insights into the uniqueness of nociceptive neurons, with each supporting an axon/dendrite of up to 50 cm
in length (which lacks a myelin sheath) and lasting a lifetime. Furthermore, these painlessness genes are starting to provide
new therapeutic avenues for pain control, for example, NGF and NaV1.7 antagonists.

Key Concepts:

Pain is the only one of the senses ubiquitously present in all multicellular organisms.

Pain has roles in both normal development and also in the prolongation of each individual through injury avoidance and management.

Mendelian disorders of painlessness exist and are individually very rare.

The study of Mendelian disorders of painlessness has led to significant advances in our understanding of pain processing and
defined a subset of genes/proteins, which are nonredundantly necessary for the generation, function and survival of nociceptors.

Biallelic mutations in either NTRK1 or NGF lead to a failure of nociception system development and congenital inability to perceive pain.

The role of voltage‐gated Na+ channels in the generation and conduction of action potentials along the peripheral nerves to central terminals. The stimulation
of pain‐sensing nerves causes an increase in the activity of NaV1.9 and NaV1.7 Na+ channels, which leads to a depolarisation of the resting membrane potential (RMP) to the threshold of action potential generation (AP threshold). At the threshold of action potential generation, NaV1.8 Na+ channels are activated and generate the majority of the action potential upstroke. The discrete activation/inactivation properties
of NaV1.7, NaV1.8 and NaV1.9 channels allow for the propagation of action potentials along the peripheral nerves to the point at which they synapse
in the dorsal horn of the spinal cord. In the spinal cord, incoming spinal afferents synapse on second‐order neurons of either
the sympathetic tract or the spinothalamic (ST) and spinoreticular (STR) tracts and ascend to central terminals where the sensation of pain is perceived.

Figure 2.

NGF/TrkA signalling during development of the nociceptive system. This figure shows a representative and simplified schematic
of developmental TrkA signalling in sensory neurons in the DRG, sympathetic ganglia neurons and cholinergic neurons of the
basal forebrain. (1) NGF is proteolytically cleaved either intra or extracellularly to remove the proregion. (2) Cleaved NGF dimers (NGFB) are able to bind TrkA and p75NTR (p75NTR increases the affinity of TrkA to NGFB) and induce TrkA dimerisation and autophosphorylation of an array of intracellular
tyrosine residues on TrkA. Although functional interaction between p75NTR and TrkA is widely accepted, the nature of their interactions as a complex with NGFB remains unresolved. TrkA/p75NTR are able to signal both at the cell membrane and as internalised signalling endosomes. Signalling proceeds through PLCγ,
MAPK and PI3K pathways to provide trophic support and differentiation cues for developing neurons. (3) Uncleaved NGF can bind sortilin through its prodomain, which drives formation of a ternary complex with p75NTR. Signalling from this complex induces cell death. Mutation in either NGF of NTRK1 results in the absence of the trophic cues required to drive differentiation and development of TrkA‐expressing neural precursors,
whereas the apoptotic signalling branch remains intact.

Figure 3.

The cellular pathology of nociceptor neuropathy. The known or hypothesised neuronal pathology of the reported nociceptor neuropathies
is shown. Nociceptor neuropathies are conditions that present with a loss of pain sensing secondary to the loss of small unmyelinated
nerve fibres. Such nerves also transmit temperature data to the central nervous system.

Stewart WF,
Ricci JA,
Chee E,
Morganstein D and
Lipton R
(2003)
Lost productive time and cost due to common pain conditions in the US workforce.
Journal of the American Medical Association
290:
2443–2454.